Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system (CNS). GABAA receptors are ligand gated ion channels that are made up from a large range of different subunits (α1-6, β1-3, γ1-3, δ, ε, π, and θ). Each receptor complex comprises five subunits, with the dominant in vivo combination thought to be 2α2β1γ. Several therapeutic agents exert their effects by modulating this receptor complex, but adverse effects, particularly sedation, are common and, in part, a consequence of poor subunit selectivity. The existence of a large number of different GABA-A receptors resulting from subunit heterogeneity indicates that there are excellent prospects for developing more selective drugs for the treatment of CNS disorders with reduced side effects. To date, the majority of the ligands that have been identified bind to α subunits that are sensitive to classical benzodiazepines, namely α1, β2, α3 and α5. Without exception, these ligands bind allosterically to the receptor, rather than by occupying the orthosteric (GABA) site and can exert a range of pharmacological activities including agonists, antagonists, partial agonists, and inverse agonists.
Agents that bind or interact with the modulatory sites on the GABAA receptor complex, such as the benzodiazepine receptor, can have either an enhancing effect on the action of GABA, i.e. a positive modulatory effect of the receptor (agonists, partial agonists), an attenuating effect on the action of GABA, i.e. negative modulation of the receptor (inverse agonists, partial inverse agonists), or they can block the effect of both agonists and inverse agonists by competitive block (antagonists or ligands without intrinsic activity).